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Flipper, keep in mind that this is an area where Pyrrho has a great deal of experience; that is, making poor pics as an individual investor.
While I believe recent history supports that, I worry that he is right about the reason for this screening hold. It is the simplest explanation that fits the statements in the SEC docs, etc..
At the same time, also moving to the simplest explanation, you have to be very concerned that BP has influenced the FDA in this decision. BP passed on the autologous immunotherapies due to the production expense, and has probably been hand-in-hand with the insurance companies, fighting against them every since. That is not conspiracy theory. That is very likely what is going on, and it needs to be looked at very closely. If they are serious about a moonshot, then they have to be serious about this kind of issue.
My apologies for distracting from the very cool DC Mfg / German patent grant news and related research provided by RK. Very impressive research. I hope it proves to be as major as it sounds like it might be.
I take it the issue with Optune would really be if Optune+TMZ+Radiation became SOC. Even if that came about I hope the only reason to disallow the addition of another component to the SOC cocktail would be a concern that... in this case, Optune or DCVax-L might lose efficacy if DCVax-L is added to the mix.
Orphan designations are different and allow profit / exclusive market guarantees as an incentive to spend the money to develop drugs for them... but regular indications... I hope it doesn't work that way.
And what are the chances that Optune would make DCVax-L ineffective, or visa versa? I would at least think that theoretical considerations would be enough to prevent the need for a new Phase III if Optune became part of SOC, unless there is some theoretical consideration that suggests a reasonable chance of an interference of some kind.
I realize you said that you thought it was probably not an issue, but just thought it was worth talking further about anyway.
The FDA insisted on adding crossover. If what you are suggesting is happening, somebody should look at that carefully. That the FDA did not want NWBO to use PFS as the primary endpoint is in no way justification for removing the net; that of a clean OS as the secondary endpoint.
I say this needs to be looked at very closely if real progress in the advancement of cancer therapies is to be made. Maybe a To-The-Moon-Shot is in order.
Yes, about a year ago, I read an article Flipper dug up about mini lymph nodes located near tumors. I had written to NWBO docs about the possibility of transplanting a lymph node to be near a tumor. They said no such had ever been proposed or tried. Then Flipper came up with that article about 6 months later. Not highly related, but related.
Of course not clear whether a lymph node could survive such a transplant, but no reason to assume it would not. You just try it. They remove lymph nodes all the time to check patient status, since there are roughly 500 in the body, they consider loss of 1 not a big deal, apparently.
A key question I posed to you which you answered indirectly; I would like to push for a direct answer:
Are you saying that when macrophages consume activated DC's, they preferentially consume the ones activated with self antigen over the ones activated with neoantigen? I kind of doubt that, but if you say you know such to be true I will give it some credence.
Not the same issue as macrophages preferentially consuming DC's that are not activated over those activated. The activated DC's travel faster than the ones not activated, so the slow ones are probably more vulnerable to macrophage attack than the fast ones. This wouldn't even require the macrophages to know the difference. At any rate it is a different issue than the macrophages distinguishing whether the DC activation is by a self antigen or a neoantigen.
I am almost certain that the DC's do not know the difference or behave differently based on whether they are activated by a self antigen or a neoantigen. Whether the macrophages can make the distinction is a different question, but I doubt that they can.
The neoantigen activated DC's are not faster than the self-antigen activated DC's.
I'm sure every long here wants to make money, but there really are a very large number of longs here that care as much or more about DCVax's seeing it through the trials. Highwayman is an MD. I am sure he is one of the many longs that cares a great deal about the science.
You are the one that accused md of being a fake. Highwayman, a fellow md, was just giving you a bad time about it since it appears you were wrong. Seems reasonable to me.
Most of the longs here that post often have been long for years. They knew from the beginning that their investments would not mature for quite a while. Some have been here long enough to be angry about enormous dilution and reverse splits, but most have been here about 2 or 3 years, over which dilution has been maybe 2 fold. That is not that radical given the potential reward.
The current situation is consistent with impending doom and impending fantastic news. Silence is standard in the first case and usually forced in the second case.
Different kind of runway. I meant a regulatory and mfg volume runway, starting with careful baby steps of validation of new process prior to mass quantities in the real world after release. Not sure if what I was saying really fit their discussion, however.
And I would agree that Woodford meant a different kind of consistent funding. Happy modicon, with a tear.
RK, this is pretty simple. Orders of magnitude more simple than your posts. I have long understood that neoantigens are natural targets for killer T-Cells. The subgroups have nothing to do with that. This is true for all cancers.
The issue is that Prins said in the Q/A after his recent lecture that the next area of focus is reducing the disadvantage that results from going after all the lysate antigens, rather than just the neoantigens. he didn't say that the reason it was an issue was due to DC migration pathway crowding, but since Pyrrhonian recently brought up that issue regarding some recent findings, and the two issues would be consistent, I am wondering if that is the mechanism that creates the disadvantage that Prins spoke about.
Prins does not say this is a huge issue, he just says it is the area next needed improving.
Maybe the reason that DCVax-L DC's taking up tons of useless self-antigen in addition to valuable neoantigen is less than optimum has nothing to do with DC migration pathway crowding... but it would make sense if that turned out to be the reason.
At any rate, focusing on isolation of neoantigens is what Prins says they are working on.
The fact that the T-Cells respond only to neoantigens does not help the DC's in DCVax-L getting overwhelmed by having to pick-up so many self antigens, which is apparently somewhat the case according to Prins. The T-Cells are step B. We are talking about Step A. Step B makes this issue in Step A a non-issue, on paper, sort of, but apparently, in the end, it is not a non-issue, according to Prins.
They'll be missing us come Monday!
Just responding to the general notion Pyrrhonian. If they had any kind of changes that related to large scale mfg, they might want or need to validate those changes before approval. That is, if a desired approval would obligate them to ramp up quickly in production, and if that would be a nightmare for them for some reason without... say automated mfg, then they would want to do everything possible to get permission to ramp into that situation before said approval. It would provide a runway. Sort of.
Out of place? I'm not even a bio guy Doc, and you apparently are. You are probably a real M.D.. Your feedback is certainly welcome.
But do the macrophages select only self-antigen activated DC's to phagocyte/eat/pacman? If so, that would be great! That would help the alleged crowding of the DC pathways.
T-Cells know the difference between a self antigen and a neoantigen... ie they know only neoantigens and ignore self antigens. DC's, unfortunately, do not know the difference, as far as I know. If there is a congestion problem in the migratory pathways during DCVax-L treatment, then that is likely the reason. But Macrophages... do they know the difference between DC's programmed for self antigens and DC's programmed for neoantigens?
Regarding the multiple low dose administration of DCVax-L, I guess the remaining question would be whether they just reduced the alleged problem of congestion of the DC's during migration, or did they effectively solve the problem?
I don't see anything in the patents or the many other links related to isolating neoantigens in tumor lysate.
Which DC bottleneck dominates? In reference to previous post.
If the DC pathways or lymph nodes were being overwhelmed by DCVax-L's large number of self-antigen programmed DC's, then NWBO would likely have found continually increasing efficacy with increasing injection sites. They may have increased the number of injection sites at some point, but if they became comfortable with some relatively small number of injection sites, then neither the DC pathway, nor lymph node crowding bottlenecks likely create a large problem. The remaining bottleneck is in DCVax-L's favor.
This argument assumes that the number of injection sites for DCVax-L was not limited in some major way, counter to efficacy considerations, by patient comfort issues.
On DC/Immune bottlenecks. Three bottlenecks referenced in recent posts and posts a couple months ago.
1 Bottleneck works in DCVax-L's favor over single antigen strategies, 2 work against DCVax-L's strategy. Unknown which of these bottlenecks dominates the picture. Not saying that DCVax-L doesn't work, just saying that if it does work, it is possible that the elimination of the two possible bottlenecks might dramatically increase efficacy.
Bottleneck 1) Pyrrho pointed to based on a DC (lysate?) study conclusion post analysis. After ex vivo antigen uptake DC's are injected near lymph nodes, with intent to travel to lymph nodes. Presumably there is a traffic jam at this point due to the high number of DC's and a finite number of pathways. If so, one might guess that the more sites you inject, the less this problem. This traffic jam could be seen as a result of generating DC's programmed with the very large number of self antigens in the tumor lysate that are not useful.
Bottleneck 2) Even if there is not a T-Cell pre-programmed for literally every possible neopeptide, there are T-Cells pre-programmed for an enormous number of different types of neopeptides. If one assumes that this number of T-Cell types is so large that it limits the number of each type that could possibly be in reserve in the Lymph nodes, then you would likely bottleneck at the lymph nodes if you try to activate a large number of DC's with the same neoantigen. This favors DCVax-L over most competing DC therapies.
Bottleneck 3) Regardless of the reason for mass quantities of DC's, if a large number make it to the lymph node then you could imagine somewhat of a traffic jam there. Thus large numbers of DC's programmed with self antigen in DCVax-L could be a problem both on the way to the lymph nodes and at the lymph nodes.
1) and 3) do not help DCVax-L, but that doesn't mean it doesn't work. It just means that if they can find a way to reduce the number of DC's programmed with self antigen, they might see a big jump in efficacy, even if efficacy is already good.
2) is already in favor of DCVax-L with no changes, at least in comparison to DC vaccinations that concentrate on a single or a small number of antigens, whether neo or not.
Interesting that the marketing for the CM's/BI's consistently uses the broad stroke description, "Immunotherapy" which has the warm and fuzzy for all the unknowing. Yet it was easily predictable from the day these therapies were a sparkle in BP's eyes that there would be horrible side effects, which has proven out.
These are wonder drugs, and BP deserves to be proud of them, and to benefit highly from having developed them. But the marketing is a little questionable. They are effective for a small percentage of patients and they have horrific side effects for about the same percentage. They make sense only for cancers that have no good options. In spite of these major limitations the marketing would have you believe that they have basically found the holy grail of cancer treatments. They have not. They have deliberately Shanghaied the term "immunotherapy" because it immediately conjures the assumptions of low side effects for this product which has horrendous side effects. My hat is off to them but get the hll out of the way for the rest of the immunotherapies in development.
"The methods for detecting the appropriate cancer cell protein from the lysate for a variety of cancers, including GBM (that patent was an outcome of the Regents agreement to write the IND and come up with GMP guidelines). "
Your saying they have patents on methods for isolating the neoantigens in the lysate? At the end of the Prins video, or in the questions after (the next video) Prins talks about the desire to do this, but he only spoke about T-Cell extraction, etc.. as far as I know.
It occurred to me when the topic of neoantigen isolation in the lysate came up, that this might be where Pyrrhonians DC pathway bottleneck shows it's head. There are so many self-antigens for every neoantigen, that the number of DC's required to address the undifferentiated bulk of antigens might overwhelm these DC travel pathways. According to Pyrrho's interpretation of the post analysis of one failed product, that is what they concluded was the primary problem.
If they could pick out only the neoantigens in the lysate then this issue would be much relaxed as would related crowding issues at the lymph nodes.
This past week I have been emailing Les my big ideas on how to possibly accomplish this isolation. Very likely a waste of his time. But you are saying that UCLA has methods already developed? Are you saying that DCVax-L already uses those methods?
"I think I drank my life-time quota in my thirties."
I too total the tea or maybe NA St Pauli Girl if I have to pay rent in a bar to see a game I can't get on my Tv; for the same reason. Lucky to have lived through my ... through thirties.
"may make manufacturing changes without conducting additional clinical efficacy studies if comparability test data demonstrate to FDA that the product after the manufacturing change is safe, pure, potent/ effective."
This patent is about the DC's, not the lysate end of things, right? So the safety end of the new techniques may have been confirmed in the Direct trial, where they are allowed to play with such things and where patents may not matter, even outside of the US.
A little harder to explain efficacy verification since Direct and L are not the same process, but maybe the relevant issues are just transparent enough that regulators allow leukocyte and cytokine, etc., measurements to be evidence enough that efficacy will not be less with L using this process.
Or, if as some suggest they were already using this tangential flow process for the DC's in L, then maybe the above considerations persuaded the FDA and other regulators to allow this.
"The excellent news is the process is now complete, and within a couple of days we should hear news that all is fine, assuming that is what the screening halt was about. All claims have been satisfied and updated as of Wednesday, May 25, 2016."
That would be wonderful RK. Even if it doesn't happen sounds like you have really been on top of this.
Hope I didn't miss any key points: But I wonder if they decided they want the remainder of the patients to come from Germany due to allowed TMZ regiment changes, and wanted this new mfg method for the DC's... so that any confirmatory would have a group with the mfg process they want to use immediately after approval or early approval or AA or whatever... but as you say, Germany was waiting for this patent to allow the use of this mfg method.
This is putting together some of Flippers input with your input. In this case the regulators would have given the nod to the mfg method provided there is a confirmatory group, albeit small, but they did not yet give the nod to the change in the TMZ regiment... or perhaps a nod only in Germany. Thus this last group would serve as both confirmatory for the mfg method approval and as more data for later arguments about the TMZ regiment for all countries/regulators.
If so, the when lifted, screening, if any, will happen only in Germany. Though Flipper spoke only about the HE patients as having the option to tweak SOC, in this case probably TMZ. Are those HE patients part of the main trial group in spite of having the option to tweak SOC?
Thank you Sentiment. I remember that you transcribed a video, but forgot it was the Prins video. And such a long video. Wow, again!
My last bullet. I am sure Afford will be happy about that. Used to drive him and others nuts when I got posting so many long posts per day. And that was back when max was 10 posts per day...
But how much random variation in TMZ use will they have to work with in the DCVax-L trial data? Unless the Germans did a deliberate study of their own inside of the DCVax-L study, it would seem unlikely that they would gain as much knowledge as even a small study dedicated to that task.
But you said you think the Germans had a head start on the issue from previous work, right?
Neoantigen does sound better than non-self antigen. So there is a name, I stand corrected.
Yes Forbes not Bloomberg. Somebody already corrected me. My apologies again to Bloomberg.
Only 2.5 Mo OS improvement with TMZ via Stupps? I thought it was more than that, but I trust you on it Flipper. That does mean that for the methylated crowd that is more like 6 months.
When I have complained about no work being done up front to find out the best TMZ regimen, (ok, if any) when in conjunction with an immunotherapy, I am not criticizing NWBO or LL. My assumption has been that they were forced to use SOC, even if the Germans or others were not. And for that reason, they did not, or probably could not do the extensive testing that would have been required to find the optimum, modified TMZ regimen for use with DCVax-L. An optimum that is very likely dependent on methylation status, with the optimum for the unmethylated likely being no TMZ.
But I do criticize the broader oncology realm for not keeping this somewhat predictable issue in debate and in the forefront of research to grease the wheels for the upcoming immunotherapies, I suppose mostly for GBM. But TMZ does get used for other cancers, and there are similar issues for other chemotherapies when used with other immunotherapies.
For anyone as confused about the antigen vocabulary as I have been at times in the past, this is my current understanding:
1) They haven't yet invented a word for amino acid sequences that the body sees as foreign. So they call them non-self antigens.
2) As you can see from 1), antigen doesn't mean cancer. It doesn't even mean foreign. It just means a protein sequence in the context of being a target for a complementary immunological entity, even if no such entity exists.
3) Mutations are not necessarily foreign. An amino acid sequence that is common in the body can mutate to another amino acid sequence that is common in the body. (Rather, the DNA section used to make the common/self amino acid sequence can mutate to produce another self sequence.) In fact, that might happen more often than mutating into a foreign / "non-self" sequence. But only non-self sequences are detectable by the body as problematic. Prins references a process in the Thymus where nacient, apparently randomly programmed T-Cells, before being released to the body, must undergo testing by some monstrous master cell. This cell presents to the T-Cell all amino acid sequences that are part of that person's genetic code, and if the T-Cell binds to any of them, this master cell kills the T-Cell, and does not release it. This would seem a very slow process, but it is what I was told goes on by an immunology researcher, and it is what Prins describes briefly.
4) The model I had perhaps assumed, was that every possible non-self amino acid sequence has some T-Cell programmed to recognize it as a non-self mutation, and to kill the cell associated with it. However, according to a study that Flipper or someone else recently posted... or was it the Prins video... not all foreign foreign sequences are covered. Maybe this is only true after the assault of SOC, or after living many years and losing some of the original set of T-Cells to various disasters such as free radical attack. But maybe the immune system does not generate T-Cells for every possible non-self amino acid sequence to begin with. It certainly generates a lot of them... but maybe not all.
5) I don't what constraints there are on peptide / sequence length when I say all amino acid sequences. I don't know if that is a specific length that the body looks at, or range of lengths... not sure. But the processing of these sequences for presentation on the cell wall for inspection by the immune system is pretty formal. One of the recent videos was clear that just random non-self sequences floating around do not get the attention of the T-Cells. Maybe macrophages pick them up and formally present them, but then again, there are rules in this presentation. There is packaging and a co-factor adjacent, apparently for docking by the T-Cells. And there may be a restriction on length. Maybe there is a very specific length that is always prepared. Not sure what effect this would have on the range of possible non-self antigens detectable... but at least anything smaller than this length might go un-noticed.
Wow! Is that wishful thinking, or are you pretty sure that is the reason? If that is the reason... wow!
Regarding ICT-107, and Celldex's antigen, as well as TPIV's antigens... aren't these all highly expressed self antigens? They may be expressed because of mutations, but these are not non-self antigens, correct?
For quite a while I have wondered about this in the back of my head when the companies talk about "highly expressed by the cancer/tumor" which sounds like the same peptides are present on some normal tissues. On the islets of the pancrease? On some other key component in the body? How many such key components exist in the body?
So... are they making antibodies to attach to these self-peptides to make them targets, or is their some minor affinity by T-Cells, Macrophages, etc for these self antigens?
Prins talks about non-self antigens having much greater affinity for T-Cells, etc, but his statements seem to allow that there can be some affinity for self antigens... or is that only if you first target the self antigens with a synthetic antibody that then labels them as targets?
This is an important and basic area, and I don't know much about it. I am sure some of you do.
Note that DCVax-L and Direct type approaches do target non-self antigens, which Prins points out is far more effective than trying to target over-expressed self-antigens. But since self antigens should not be a target at all, this leaves the question of what is Prins talking about, and why are these other companies bothering? A question which very likely has some reasonable explanation.
Thanks Longfellow: Nice to see that in print. It would be nicer to see it in an official trial protocol doc, but assuring to see it in print.
"-Trial designed to reach p value = 0.02 if 4-month difference in PFS shown."
"-Multiple subgroup analyses were prospectively included."
Longfellow: "So, theoretically, they could recommend an efficacy halt for a subgroup at any point (mesenchymal?)"
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If I read this correctly, and if p value is linear with population (which it may not be), then they are powered for a 40% subgroup to reach a p value of .05 if it only shows 4 months improvement in PFS. I believe the mesenchymals are about 40% of the population. So only 4 months PFS improvement by the mesenchymals might be enough for approval... if the trial was fully enrolled and mature, which it is not. But... it is mostly there regarding 4 months PFS or better, right?
So we are back to where I thought we were two weeks ago when some revelations, that were accurate, but incomplete, scared the heck out of me. Thank goodness! Thank you longfellow.
I guess there is the assumption that mesenchymal was one of the subgroups they are talking about. It might not be. But you would think it was. And if not, since it is a universally agreed upon subgroup, and the early trials showed a long mesenchymal tail... if they wouldn't consider high efficacy in that group I would sure push them to consider all aspects of the rules and stochastics to make sure such exclusion is not a mistake from some higher level perspective be that mathematical or human.
My apologies to Bloomberg.
Yes, I didn't mean data feeds, ie this post. But your post yesterday about checking the Bloomberg data came right at the tail end of a discussion about Bloomberg maybe going to the dark side as a source... again likely only effecting subjective reports, if any, not data feeds.
If cooperation in cancer research is the primary focus for the Moonshot program, and of this upcoming summit, then shouldn't cut-throat undermining of cancer development efforts also be a prime focus, Joe?
That is a lot of green! It appears you do have access to Bloomberg data (inyofc coman).
Though after the discussion yesterday about ownership changes for Bloomberg... you might be leery of any subjective reports!
RK: One other point. If they did change the WBC criterion in 2014, then I would think that the addition of WBC as a covariate might allow them to massage the data to model the results that would be expected if the criterion had been implemented from the beginning. That's not much help if the new screening does not favor the experimental group, but it might, particularly in terms of PFS, if the pseudo's are properly identified.
I'm not talking from experience here. I am just going from what I read about covariates in a post that Senti's wrote yesterday.
I think it was Exwannabe that argued that covariates do not get used very much because the FDA recognizes that they can easily be abused. But that doc that Senti posted stated clear constraints that force covariates to be only of transparent utility and for the intent of their use to be stated up front. The utility of Methylation as a covariate would be straightforward, so I don't see how the FDA could have a problem with it. On the other hand, WBC would seem less clear. But I would hope that the WBC screening for an immunotherapy would at least be recognized as a very important factor and worthy of discussion in post analysis, even if the effect of that screening parameter is not 100% predictable. It would not be in the category of just adding a bunch of variables so you can pick out some random peak in the post analysis. The FDA would have to watch out for such, but it is a totally logical consideration and I believe the FDA would recognize that. In fact, the apparently did because if it was added to the trial then it was approved by the FDA... right?
Thanks RK. Lots of good stuff. I read it all but will have to read it all a couple more times to get the most out of it.
I posted too much yesterday and too long of posts, so trying to not do that today. But as I re-read your post here, one thing I will be trying to understand is why you worry that improved SOC may have benefited the control group more than the experimental group. Perhaps it is your explanation for a less than expected gap in SOC that LL references. I actually forgot she had said that.
Other questions before I re-read your post: You said...
"They may have not told us outright in 2014, but I believe they changed the lymphocyte count “inclusion” criteria after six weeks of chemoradition. Those blood cell counts can make a difference of 6 months in OS even before immunotherapy is introduced. And that kind of "inclusion" change will affect both arms before and after crossover. After crossover is where it will be seen most in immunotherapy. The less comprised and immunotherapy patient is going into an immunotherapy treatment, the better off they will do."
I thought they changed that WBC criterion also, but I can't remember why I thought that. Why do you think they changed it? I worry too that it might not benefit the experimental group more than the control group, even if they did not have crossover. An intact immune system is always a good thing, just a question of how much of a good thing. But I was very much in favor of having such a criterion because it seems unfair to test an immunotherapy on patients that no longer have a healthy immune system...
But again, I share your concern that it could help the controls also. Your point about crossover is based on the late point in SOC that the WBC criterion gets considered? Another angle of concern might be that since macrophages apparently provide early warning to raise PD-1 or L1(?) flags, introducing DC's into a stunned (but not dead) immune system might comprise a surprise attack that is more effective than if the immune system was healthy, at least in regards to macrophage activity. That is... if the stun state still allows DC migration and T-Cell activation and migration... while the macrophages remain dormant. Timing may be everything as the Italians stated, but the optimum timing may be even more complicated than their study indicated.
All could be tweeked down the road if DCVax-L passes, however, and hopefully reimbursement re-negotiated if efficacy increases in response to any such tweeks. But I don't know if it works that way. But even if not in the past, maybe this environment of tech moving so much faster than trials will allow such policies in the future.
Flipper: Regarding covariates: I do have a little bit of traction now, and understand that they can be used to correct for enrollment subgroup distribution imbalance. I see how they could do that and why they would want to do that, but I also see how the implementation of covariates could be a big advantage in the case of any important screening changes that were implemented after the trial started.
Was there a change to the white count screening criterion at the point that they expanded the trial and reduced the PFS bar? I remember there having been a change, but then again, I remember them adding subgroups at that point, which Reefrad pointed out, did not happen.
If it turns out that covariates are only to be used to correct the data in post analysis; to balance relevant, pre-defined subgroups between the arms, then that would sound like a very minor positive effect. In fact, the effect would not necessarily improve the outcome of the analysis. The chance of a positive vs negative correction would be equal. But it is still a good thing. Better to fail because there was no efficacy than fail when there was efficacy, but a statistical anomaly had a large excess of the methylated in the control arm... for example.
...again, if I am understanding how covariates are used.
However, this is a unique situation. There are covariates listed that relate to the health of the immune system. This means that not only did they stop allowing patients with severely damaged immune systems into the trial at some point, they have built in the ability to compensate for such patients that were allowed into the trial prior to the screening change. (There was a screening change, right?) That is, assuming the patient screening data prior to any such screening change would have been sufficient to do the screening in the past, they can essentially do the screening retroactively. If the patients with more intact immune systems do better, they will be allowed to project what the trial results would have been if they had started this screening of immune system health from the beginning.
Or, if there was a change to this aspect of the screening, the covariate allows them to project what the results would have been if the change had been part of the original trial protocol. At least, if they did not list the covariate, they would not be allowed to do this. Not sure that listing it guarantees that they will be allowed to do it in post analysis.
But I only made it through 1/3 of the article.
Thanks Sentiment. This is the first good paper on covariates that I have seen posted since the topic started or restarted recently.
I probably got about as much out of that definition as you... . The first 1/3 of the article makes me wonder if the covariates are only intended for use in tweaking the data in the post analysis. Maybe not, but so far, that is what it sounds like. Not the same as subgroups.
If it turns out these are for tweaking the data, it would likely be to make sure... for example, that both arms of the trial had the same percentage of methylated patients. Rather... it would be second order tweaking of the data to compensate for any difference in that count. If there was no efficacy difference between methylated and not methylated, then there would be no need for the tweeking, but if there was a difference, as expected, then the correction would be pretty straight-forward. It would be recursive, but not complicated. Other variables might not be as easy.
Sounds like you are saying that I am trying to jump on the Temador issue bandwagon at a late stage. If so, Flipper will tell you I was trying to get to the bottom of that issue long before you started posting. I change my view with everything I learn. In the beginning, close to 3 years ago, I ran across an article that said that many patients die from the Temador. That angered me as it all looked like a big pharma chemo conspiracy. Since that time my perspective has evolved, right or wrong, and it appears to me that the optimum dosage of Temador for the methylated patients, as a monotherapy, would have about half dying from the Temador, and half dying from the cancer. Sort of. They really don't separate into distinct groups like that. But I see now that this would have actually been the right dose, if patient quality of life is ignored. Not sure how bad the side effects of Temador are besides the damage to the immune system, but brain cancer has some pretty nasty side effects of it's own.
But what about the patients that don't respond to Temador, the un methylated? If identifiable up front, then why damage their immune systems using Temador. Maybe they can't identify them soon enough, or maybe it costs an extra $50 and the insurance companies who have stock in the BP (I forget which) that mfgs Temador don't want to pay the $50.
Probably not, but prima facia it is a horrible history that is still SOC. I have brought this up for maybe 2 1/2 years, including emails to NWBO repeatedly, and I have never heard a reply or a post that explains why unmethylated patients are given Temador.
And further, for a similar period of time, I have pointed out that for the methylated patients receiving an immunotherapy like DCVax-L, Temador is apparently very helpful, but the amount of Temador that is optimum is very likely less than what is optimum without the immunotherapy.
I don't claim to have supported NWBO over all those years like you and Flipper. For much of that time I had lost most of my shares, and was focused elsewhere intent on getting ahead to buy back my shares. At this point I have done so, sort of.
One of the more effective bash articles against NWBO was written by a known author, supposedly working in China at the time. I think it was Pierce. I could have the wrong guy. This was quite a while ago. Maybe 19 months ago?
I don't know, but that sounds like a lot of Temador. Sounds like too much of a good thing for the methylated patients and way too much of a bad thing for the unmethylated patients.
"10155 is their booth from last year"
Oops. Sorry about that.